tbuckley/cabot-search huggingface dataset:
Phase II trial of lurbinectedin combined with avelumab as maintenance therapy for metastatic urothelial carcinoma with stable or responding disease following platinum-based chemotherapy.
Authors: Guru P. Sonpavde, Carlos A. Alemany, Wassim Mchayleh, Julie W. Pepe, Susan Coakley, Ashley Young, Rohit K. Jain
Journal: Journal of Clinical Oncology (2023)

TPS590 Background: Maintenance avelumab following stable/responding disease after 4-6 cycles of platinum-based chemotherapy is a conventional first-line therapy for metastatic urothelial carcinoma (mUC). Given the attrition of patients between lines of systemic therapy, there is a role for extending the benefits of maintenance avelumab by combinations with tolerable and active agents. Lurbinectedin (Lurbi) is an alkylating agent and selective inhibitor of oncogenic transcription. Lurbi is approved by the US FDA for treating small cell lung cancer with progression on platinum-based chemotherapy with typical dosing as 3.2 mg/m 2 intravenously (IV) every 3 weeks. The activity of lurbi in the presence of DNA damage repair (DDR) alterations, multiple transcriptomic drivers and preclinical synergism with and feasibility of co-administration with immune checkpoint inhibitors (ICI) suggests potential activity of combination lurbi and ICI in mUC. Patients with stable or responding disease following platinum-based chemotherapy are phenotypically selected for deficiencies in DDR. Lurbi may be tolerable in this setting given mostly reversible myelosuppression and no serious non-hematologic toxicities especially neurotoxicity. Thus, the combination of lurbi with maintenance avelumab may warrant evaluation in mUC. Methods: A non-randomized multicenter (Advent Health Cancer Institute, Moffitt Cancer Center) phase II trial (n=36) is designed to evaluate combination avelumab (800 mg IV every 2 weeks) and lurbi (3·2 mg/m 2 IV as a 1-h infusion every 4 weeks) for those with stable or responding disease following 4-6 cycles of platinum-based first-line platinum-based chemotherapy for mUC. Therapy is continued till progression of disease, intolerable toxicities or patient decision. Patients are seen for a clinical examination every 4 weeks (1 cycle) with laboratory evaluation every 2 weeks. Radiographic imaging is performed every 8 weeks for 6 months and then every 12 weeks thereafter to assess disease. Premedication for lurbi includes corticosteroids (dexamethasone 8 mg or equivalent) and serotonin antagonists. Mandatory granulocyte-colony stimulating factor (G-CSF) prophylaxis will be administered to all patients. Baseline archival tumor tissue and periodic blood is collected for correlative studies (tumor genomics/PD-L1 expression, circulating tumor DNA and immune markers). Given a median progression-free survival (PFS) with avelumab alone of 3.7 months, an alternative median PFS of 6 months is of interest warranting further development. We will enroll 33 evaluable patients to achieve 90% power at a 1-sided alpha level 0.1 to detect hazard ratio of 0.62. Given ~10% of enrolled patients may be inevaluable, we may enroll up to 36 patients. Clinical trial ID: NCT05574504. Clinical trial information: NCT05574504 .
Role of epigenetic regulator <i>KMT2C</i> mutation detected by liquid biopsy in survival in patients with prostate cancer.
Authors: Nanwei Xu, Sha Zhu, Pengfei Shen, Hao Zeng
Journal: Journal of Clinical Oncology (2023)

222 Background: KMT2 (lysine methyltransferase) family enzymes exert epigenetic regulation to active gene transcription. KMT2C is mainly involved in enhancer-associated H3K4me1 and is also the top mutated gene in cancer (6.6% in pan-cancer). Currently, the clinical significance of KMT2C mutations in prostate cancer is understudied. Methods: We included 221 prostate cancer patients diagnosed between 2014 and 2021 in West China Hospital of Sichuan University with cfDNA-based liquid biopsy test results in this study. We explored the association of KMT2C mutations with other mutations and investigates the prognostic significance of KMT2C mutation measured by overall survival (OS) and castration-resistance free survival (CFS). In addition, we explored the prognostic value of KMT2C mutation in different patient subgroups. Results: The KMT2C mutation rate in this cohort is 7.24% (16/221). KMT2C-mutated patients showed worse survival compared to KMT2C-WT patients in terms of both CFS and OS (CFS: mutated 9.9 vs. WT 22.0 months, p=0.015; OS: mutated 71.9 vs. WT 137.4 months, p=0.012). KMT2C mutation was also an independent risk factor in OS [HR: 3.815 (1.461, 9.96), P=0.006] in multivariate analyses. Besides, we also explored the association of KMT2C mutations and other genes, and the results showed that KMT2C mutation was related to Serine/Threonine-Protein Kinase 11 ( STK11, p=0.004) and Catenin Beta 1 ( CTNNB1, p=0.008) mutations. For OS, KMT2C mutation was significantly associated with survival in patient subgroups with PI3K pathway mutation (HR: 6.64, p=0.009) or WNT pathway mutation (HR: 2.44, p=0.043). Conclusions: KMT2C-mutated patients showed worse survival compared to KMT2C-WT patients in terms of both CFS and OS, and KMT2C mutation was associated with STK11 and CTNNB1 mutations. Furthermore, KMT2C mutation was significantly associated with survival in certain patient subgroups, such as patients with PI3K and WNT pathway mutation, etc.
Evaluation of miRNA-371a-3p (miR371a) assay to predict final pathohistology in patients undergoing primary nerve-sparing retroperitoneal lymphadenectomy (nsRPLND) for stage IIA/B seminomas and non-seminomas.
Authors: Felix Seelemeyer, David Pfister, Pia Paffenholz, Sabine Merkelbach-Bruse, Roberto Pappesch, Axel Heidenreich
Journal: Journal of Clinical Oncology (2023)

427 Background: NS-RPLND represents a guideline recommended treatment option in marker negative low volume metastatic seminomas and nonseminomas (NSGCT). However, about 30% of clinical stage IIA patients demonstrate equivocal findings of uncertain dignity so that they might undergo unnecessary treatment. Elevated serum concentrations of the molecular marker miR371 have been reported to correlate with the clinical stage even in small volume metastases. It was the purpose of our pilot study to evaluate the predictive accuracy of miR371 in a cohort of patients who underwent nsRPLND for clinical stage IIA/B germ cell tumors of the testis. Methods: Between 1-9/2022, 16 patients with marker negative clinical stage IIA/B seminomas (n=10) and NSGCT (n=6) underwent primary nsRPLND with a modified template resection via an open surgical approach. Blood specimens (20ml) were drawn on the day immediately prior to surgery and processed according to the manufacturer’s protocol. miRNA is extracted and purified with the Maxwell RSC MiRNA Plasma and Serum Kits prior to its transcription into cDNA using cDNA Solution, Reverse Transcriptase and RNase Inhibitor. Subsequently, this cDNA is amplified. Using qPCR techniques, the miRNA 371a is quantified using Roche Lightcycler 480 II. Using the Lightcycler software, the median Cp (CP = crossing points) of the triplicates is calculated and converted into a RQ value (RQ= relative abundance). Results: nsRPND was performed in all patients without significant Clavien-Dindo IIIa-V complications. Mean OR time was 131 (105-195) minutes, mean blood loss was &lt; 150ml, transfusion rate was 0%. Mean number of dissected lymph nodes was 17 (7-32), mean diameter of positive lymph nodes was 2.1 (0.8-4.1) cm. Histology revealed metastatic seminoma or nonseminoma in 12/16 (75%). In 4 patients histology revealed non-malignant disease (n=2), teratoma, and lymphoma. miR371 was positive in all 12 (100%) pts with metastases and it was negative in 3/4 (75%) pts without metastases. One patient with small volume CS IIA seminoma was false negative. Conclusions: This is the first report to demonstrate that miR371can be used as a personalized and individual biomarker to predict the presence of small volume retroperitoneal lymph node metastases in CS IIA/B seminomas and in nonseminomas. Patients with positive findings should undergo active treatment whereas negative findings should result in close follow-up. Date are currently validated in a multi-institutional trial.
Prognostic value of C-11 choline PET/CT scan in patients with metastatic castration resistant prostate cancer (m-CRPC) undergoing treatment with radium-223.
Authors: Matthew Lee, Mohamed E. Ahmed, Eugene D. Kwon, Ayse T. Kendi
Journal: Journal of Clinical Oncology (2023)

59 Background: Radium-223 (Ra-223) has been approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) with predominantly osseous metastases. PSA flare phenomenon with Ra-223 limits the use of PSA as a prognostic tool to predict treatment response. Currently, there is a lack of diagnostic tools to predict treatment response to Ra-223. Therefore, we sought to investigate the role of mid-treatment C-11 choline PET/CT scan in predicting overall response to Ra-223. Methods: In a single institute retrospective study, we identified 32 patients who were treated with a full course of 4-6 cycles of Ra-223 and were evaluated with both PSA and C-11 choline PET scan before treatment, at mid-treatment, and after a complete course of Ra-223 between 2013 – 2018. Ra-223 was used as salvage therapy for their predominant bone disease after failing chemotherapy and 2 nd generation hormone therapy. Blind repeat radiographic evaluation of patients’ scans was performed by a radiologist specialized in nuclear radiology. Favorable response was defined by achieving partial response or stable disease on imaging, while unfavorable response was defined by showing progressive disease on imaging. Results: Mean age (±SD) at starting Radium223 was 67.6 (±7.1) years, median (IQR) primary Gleason score was 9 (8-9), and median (IQR) pretreatment PSA was 13.5 (5.4-39.6) ng/ml. 78% of the patients (n=25) completed 6 cycles of Ra-223, 15% of the patients (n=5) completed 5 cycles, and 6% (n=2) received only 4 cycles. At mid-treatment scanning, 25% of the patients (n=8) showed favorable response (Group A), while 75% of the patients (n=24) showed unfavorable response (B). After a complete course of treatment, 62.5% of patients (n=5) in Group (A) continued to show favorable response, while only 8.3% of patients (n=2) in Group (B) showed favorable response (p-value= 0.0023). Conclusions: Mid-treatment evaluation with C-11 choline PET/CT scan can predict overall response to Radium 223. Patients with progressive disease at mid-treatment evaluation are very likely not going to respond to further treatment. Further studies and clinical trials are warranted.
Efficacy of systemic therapy following [<sup>177</sup>Lu] Lu-PSMA in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Louise Kathleen Kostos, William Yu Ching Lai, Peter Lambroglou, Elizabeth Medhurst, James Patrick Buteau, Shahneen Sandhu, Ben Tran, Lavinia Anne Spain, Ciara Conduit, Roslyn Wallace, Ramin Alipour, Timothy J. Akhurst, Grace Kong, Anthony Cardin, Javad Saghebi, Aravind Ravi Kumar, Michael S Hofman, Arun Azad
Journal: Journal of Clinical Oncology (2023)

77 Background: [ 177 Lu]Lu-PSMA (LuPSMA) is currently FDA-approved for use in the post-taxane, post-antiandrogen setting in pts with mCRPC. Little is known about the efficacy of treatment in pts with subsequent progression after LuPSMA. In this single-centre retrospective analysis, we evaluated efficacy of first subsequent therapy following LuPSMA. Methods: 234 mCRPC pts who received LuPSMA at the Peter MacCallum Cancer Centre from 2015-2022 were analysed. Pts were excluded if they did not receive any subsequent treatment (n=136), if they received the initial course of LuPSMA in combination with another therapy (n=10), or if insufficient follow-up data were available (n=15).Retreatment withLuPSMA was considered a subsequent line of therapy. Data collected included 50% PSA response rate (PSA-RR), PSA-progression free survival (PSA-PFS) and overall survival (OS). Survival outcomes were calculated using Kaplan-Meier analysis. Results: Of 73 evaluable pts, 32 were retreated with LuPSMA (median 2 cycles); and 41 commenced a new line of systemic therapy. In the LuPSMA retreatment group, the PSA-RR was 44%, median PSA-PFS was 3.8 months and median OS 14.8 months. In pts who changed to a new line of treatment, cabazitaxel was the most commonly prescribed therapy (n=25), followed by docetaxel (n=7), and single-agent carboplatin (n=4), in addition to carboplatin/etoposide, mitoxantrone, olaparib, capecitabine and a clinical trial (n=1 for each). PSA-RR was 12%, median PSA-PFS was 3.5 months and median OS 6.6 months. Conclusions: This retrospective data demonstrates that retreatment with LuPSMA is associated with benefit, though this is reduced compared to initial treatment. In our cohort of pts who commenced a new line of therapy, most were not suitable for retreatment with LuPSMA, potentially reflecting de-differentiated and more aggressive disease phenotypes. In those not suitable for LuPSMA retreatment, other systemic therapy appears to have limited benefit, highlighting the lack of effective salvage options and raising questions about treatment sequencing. [Table: see text]
Influence of molecular imaging on patient selection for treatment intensification prior to salvage radiation therapy for prostate cancer: A post hoc analysis of the PROPS trial.
Authors: Samuel Tremblay, Mofarej Alhogbani, Andrew Weickhardt, Ian D. Davis, Andrew Mark Scott, Rodney J. Hicks, Ur Metser, Sue Chua, Reena Davda, Shonit Punwani, Heather Ann Payne, Nina Tunariu, Bao Ho, Sympascho Young, Glenn Bauman, Louise Emmett, Frederic Pouliot
Journal: Journal of Clinical Oncology (2023)

316 Background: The impact of molecular imaging (MI) on patient management after biochemical recurrence (BCR) following radical prostatectomy has been described in many studies. However, it is not known if MI-induced management changes are appropriate. This study aimed to determine if androgen deprivation therapy (ADT) management plan is improved by MI in patients who are candidates for salvage radiation therapy. Methods: Data were analyzed from the multicenter prospective PROPS trial evaluating PSMA/Choline PET in patients being considered for salvage radiotherapy (sRT) with BCR after prostatectomy. We compared the pre- and post-MI ADT management plans for each patient and cancer outcomes as predicted by the MSKCC nomogram. A higher percentage of predicted BCR associated with ADT treatment intensification after MI was considered as an improvement in a patient’s management. Results: Seventy-three patients with a median PSA of 0.38 ng/mL were included. In bivariate analysis, a positive finding on MI (local or metastatic) was associated with decision to use ADT with an odds ratio of 3.67 (95% CI, 1.25 to 10.71; p=0.02). No factor included in the nomogram was associated with decision to use ADT. Also, MI improved selection of patients to receive ADT based on predicted BCR after sRT: the predicted nomogram 5-year biochemical-free survivals were 52.5 % and 43.3%, (mean difference, 9.2%; 95% CI 0.8 to 17.6; p=0.03) for sRT alone and ADT±sRT subgroups, while there was no statistically significant difference between subgroups before MI. Conclusions: PSMA and/or Choline PET/CT before sRT can potentially improve patient ADT management by directing clinicians towards more appropriate intensification.
Safety and tolerability of pembrolizumab/axitinib combination in metastatic renal cell carcinoma (mRCC): A multicentric prospective analysis (ProPAXI study).
Authors: Annalisa Guida, Marco Maruzzo, Eleonora Lai, Davide Bimbatti, Francesco Pierantoni, Michele Dionese, Giuseppe Fornarini, Elisa Zanardi, Veronica Murianni, Claudia Caserta, Claudia Mosillo, Maria Letizia Calandrella, Grazia Sirgiovanni, Fabio Calabro, Linda Cerbone, Orazio Caffo, Luca Galli, Sergio Bracarda
Journal: Journal of Clinical Oncology (2023)

688 Background: Pembrolizumab/axitinib (PAXI) combination is an approved option as first-line therapy of mRCC. The aim of this analysis is to evaluate safety profile of PAXI combo in the real-world experience in Italy. Methods: This is a prospective study including patients (pts) diagnosed with mRCC who received PAXI as first-line therapy in recruiting Italian Centers. Safety data about clinically significant adverse events (AEs), defined as AE requiring corticosteroids, hormone replacement, drug delay, discontinuation or dose reduction were collected. Results: Data from 122 pts treated from January 2021 to September 2022 have been analyzed. With a median follow-up of 10 mos (range 0.2 - 21) and treatment interruption in 35 pts (29%), at landmark 6-mos and 12-mos the treatment was ongoing in 76% (95%CI 0.67-0.83) and 66% of pts (95%CI 0.56-0.75) respectively. In 11% of pts a starting dose of Axi &lt;5mg was reported (8% higher starting dose). 2% of pts experienced Axi dose titration while 37% of pts had a dose reduction. Pts completed a mean of 10 (1 - 31) cycles of Pembro. Toxicity led to treatment discontinuation in 20% (7/35) of cases. Clinically significant AEs occurred in 61% of pts (74), managed with corticosteroids use in 32% (24/74) of pts, hormone replacement (mainly levothyroxine) in 11% (8/74), drug delay in 64% (47/74), discontinuation in 41% (30/74) or dose reduction 18% (13/74). When required, the most used steroid was prednisone (48%) following by dexamethasone (22%), prednisolone (17%), methylprednisolone (13%). Grade 3-4 clinically significant AEs occurred in 25% (18) and 3% (2) of pts respectively, with hepatic injury 33% (6/18) and hypertension 17% (3/18) as the most common reported G3 events. The two G4 AEs reported were pancreatitis and hepatic injury. No treatment-related deaths emerged. In 20% of cases AE were related to Pembro and in 47% of cases to Axi, in 14% to both drugs. In 28% of pts (34/122) a second clinically significant AE occurred, requiring corticosteroids 27% (9/34), hormone replacement 9% (3/34), drug delay 59% (20/34), discontinuation 41% (14/34) or dose reduction 21% (7/34). Grade-3 clinically significant AEs occurred in 29%, with hepatic injury and hypertension (both 3 pts) as the most common events. No grade 4 AEs were reported. The second AE in 21% of cases was related to Pembro and in 59% of cases to Axi, in (9%) to both drugs. Conclusions: PAXI combination had a tolerable safety profile in mRCC, with few high-grade clinically significant AEs, no new toxicities were identified.
US real-world first-line (1L) treatment patterns and outcomes for patients with metastatic urothelial carcinoma (mUC) following maintenance avelumab approval.
Authors: Haojie Li, Lisa Herms, Traci Leong, Paul R. Conkling, Sonia Franco, Puneet Singhal, Ronac Mamtani, Manojkumar Bupathi
Journal: Journal of Clinical Oncology (2023)

483 Background: The introduction of the immune checkpoint inhibitors (ICI) pembrolizumab and atezolizumab has dramatically changed the 1L mUC treatment paradigm. These agents are currently recommended by the National Comprehensive Cancer Network for platinum-ineligible patients (irrespective of programmed death-ligand 1 (PD-L1) status) and, in the case of atezolizumab, for cisplatin-ineligible patients whose tumors express PD-L1. More recently, avelumab, received approval as the first ICI for the maintenance treatment of patients who have not progressed on 1L platinum-containing chemotherapy. In this study, we described real-world 1L treatment patterns and outcomes for mUC patients following avelumab maintenance approval. Methods: We used electronic medical record data from The US Oncology Network, which includes 1,400 affiliated physicians operating in over 500 sites of care across states and treats approximately 1.2 million cancer patients annually. mUC patients diagnosed between 30 April 2020 (i.e., ~3 months before avelumab maintenance approval) and 30 June 2021 were included, with follow-up until 31 December 2021, last patient record or death, whichever occurred first. Chart review was conducted to verify mUC diagnosis, baseline characteristics, treatment patterns, and clinical outcomes. Avelumab maintenance was defined as receiving avelumab after 1L platinum-containing chemotherapy, with no documented progressive disease prior to avelumab start or as maintenance therapy indicated by physician notes. Results: A total of 249 eligible mUC patients initiated 1L treatment. Of these, 132 (53%) received ICI monotherapy, 99 (40%) received platinum-containing chemotherapy, and 18 (7%) received other treatments. Almost one-third (n=32) of those who received 1L platinum-containing chemotherapy received avelumab maintenance therapy. ICI monotherapy use increased with age, ranging from 36% among &lt;65-year-olds to 67% among ≥75-year-olds. During a median follow-up of 14.5 months, 68 (27%) patients received second-line treatment. Median (95% confidence interval) overall survival (OS) for 1L ICI monotherapy and 1L platinum-containing chemotherapy was 10.9 (7.2, 13.0) and 16.8 (13.5, not reached) months, respectively. Conclusions: During the 18-month period following maintenance avelumab approval, in this US community oncology setting, ICI monotherapy was the most utilized 1L treatment for mUC patients, especially among older patients. The uptake of maintenance avelumab was modest. Longer follow-up is needed to further characterize OS, especially for those who received platinum therapy followed by avelumab maintenance.
<sup>18</sup>F-PSMA1007 PET/CT in the context of biochemical recurrence of prostate cancer: An economical experience from a Latin American reference center.
Authors: Maria Paula Mogollon, Juan Ignacio Caicedo, Natalia Ramirez, Julian Rojas, Camilo Medina
Journal: Journal of Clinical Oncology (2023)

47 Background: 25-30% of patients present with biochemical recurrence of prostatic adenocarcinoma (PCa) after primary tumor treatment. One of the options indicated for the study of recurrence is PET/CT PSMA. In our center we use the 18 F-PSMA1007, which has a cost of approximately $1,342, while the alternative cost ( 68 Ga-PSMA-11) is $2,422. The aim of this study is to evaluate the performance of 18F-PSMA-1007 PET/CT in patients with biochemical recurrence after definitive therapy. Methods: A cross-sectional study that included patients with a biochemical recurrence and who underwent 18 F-PSMA1007 PET/CT in our center of reference between 2020-2022. Biochemical recurrence was defined as a PSA &gt;0.1 ng/dL in prostatectomy and a value of nadir PSA + 2ng/ml in radiotherapy. Descriptive analysis was performed with frequencies for discrete variables, and central tendency and dispersion measures for continuous variables. Detection rates were evaluated according to primary tumor treatment and PSA values. To compare categorical variables, we use Chi-square and t-Test for continuous variables. This analysis was performed using SPSS statistical software. Results: A total of 154 patients were included, 84% (n=129) with radical prostatectomy and 16% (n=25) received management with radiotherapy. Of the first group, 75.2% had evidence of recurrence on 18 F-PSMA-1007 PET/CT, while of the second group, 92% had evidence. The descriptive analysis is shown. A statistically significant difference was found in local recurrence and bone metastasis. In terms of metastases, 26,3% of post-surgical patients had bone metastasis and a higher percentage (52%) of those who underwent radiotherapy, with concomitant involvement of both the axial and appendicular skeleton in both groups. In the prostatectomy group, the detection rates for PSA levels &lt;0.25, 0.25 - &lt;0.5, 0.5-&lt; 1, 1-2, 2 - &lt; 5, 5 - &lt;10, ≥10 were 12.5%, 48.3%, 79.2%, 84.2%, 96%,90% and 100% respectively. In the radiotherapy group, the detection rates for PSA levels 2 - &lt;5, 5&lt;10, ≥10 were 87,5%, 100% and 100%, respectively. Conclusions: 18 F-PSMA-1007 PET/CT is an alternative option that offers similar detection ranges and is more economical than 68 Ga-PSMA-11 in our population, allowing effective detection of biochemical PCa recurrence in central and remote locations, where fluorine is not consistently available. [Table: see text]